Synthesis of ß-enamino malonates through caesium carbonate-promoted reaction of nitro-substituted donor-acceptor cyclopropanes.

A caesium carbonate-promoted reaction of nitro-substituted donor-acceptor cyclopropanes (DACs) with primary aromatic amines in water provides a convenient access to ß-enamino malonates under mild reaction conditions. The transformation takes place through the formation of allene intermediates from the DACs followed by the conjugate addition of various primary aromatic amines to the intermediates. The reaction proceeds more efficiently in water as compared with organic solvents and the products were isolated in good yields by filtering through a silica gel column without any prior extraction procedure.

Ytterbium Triflate-Catalyzed Intramolecular Arylative Ring Opening of Arylaminomethyl-Substituted Donor-Acceptor Cyclopropanes: Access to Tetrahydroquinolines.

The treatment of arylaminomethyl-substituted donor-acceptor cyclopropanes with a catalytic amount of Yb(OTf)3 provides expedient access to tetrahydroquinoline derivatives. The transformation proceeds through an intramolecular SN2-type attack of the aminomethyl-containing aryl ring on the cyclopropane ring, leading to the formation of the products as single diastereomers.

Synthesis of 1-aryl-2,3-diaroyl cyclopropanes from 1,3,5-triaryl-1,5-diketones and their transformation into E,E-1,4-diaryl-1,3-butadienes.

A new method for the synthesis of 1-aryl-2,3-diaroyl cyclopropanes has been developed by iodine/DBU-mediated cyclization of 1,3,5-triaryl-1,5-diketones. The alcohols derived by the reduction of these cyclopropanes, when treated with conc. HCl, afforded a series of 1,3-dienes through cyclopropyl ring-opening and subsequent fragmentation. Overall, the synthetic sequence represents a new non-Wittig methodology for the synthesis of 1,3-dienes from 1,5-diketones.

Intramolecular 1,2-Aroyl Migration in Spiro Donor-Acceptor Cyclopropanes: Formation of 1,4-Naphthoquinones and 1-Naphthols as Ring-Expansion Products.

Most of the known rearrangement reactions of donor-acceptor cyclopropanes (DACs) involve the migration of cationic carbon atom to anionic carbon or heteroatoms in 1,3- or 1,4-positions. In the present work, we observed that spiro DACs based on 1,3-indanedione or 1-indanone moiety undergo intramolecular 1,2-aroyl migration when treated with titanium(IV) chloride to afford 1,4-naphthoquinones and α-naphthols readily. The reactions take place through the formation of putative 1,3-dipolar intermediates, followed by cleavage and migration of the aroyl group to the adjacent carbon to afford the ring-expansion products.

Evaluation of dual potentiality of 2,4,5-trisubstituted oxazole derivatives as aquaporin-4 inhibitors and anti-inflammatory agents in lung cells.

Inflammation is a multifaceted "second-line" adaptive defense mechanism triggered by exo/endogenous threating stimuli and inter-communicated by various inflammatory key players. Unresolved or dysregulated inflammation in lungs results in manifestation of diseases and leads to irreparable damage. Aquaporins (AQPs) are a ubiquitously expressed superfamily of intrinsic transmembrane water channel proteins that modulate the fluid homeostasis. In addition to their conventional functions, AQPs have clinical relevance to inflammation prevailing under the infectious conditions of various lung diseases and this proclaims them as appropriate biomarkers to be targeted. Hence an endeavor was undertaken to identify potential ligands to target AQP4 for the treatment of lung diseases. Oxazole being a versatile bio-potent core, a series of 2,4,5-trisubstituted oxazoles 3a-j were synthesized by a Lewis acid mediated reaction of aroylmethylidene malonates with nitriles. In silico studies conducted using the protein data bank (PDB) structure 3gd8 for AQP4 revealed that compound 3a would serve as a suitable candidate to inhibit AQP4 in human lung cells (NCI-H460). Further, in vitro studies demonstrated that compound 3a could effectively inhibit AQP4 and inflammatory cytokines in lung cells and hence it may be considered as a viable drug candidate for the treatment of various lung diseases.

Cesium Carbonate-Promoted Reaction of Nitro-Substituted Donor-Acceptor Cyclopropanes with Salicylaldehydes in Water: Access to Chromane Derivatives.

Nitro-substituted donor-acceptor cyclopropanes react with salicylaldehydes in the presence of cesium carbonate in water to give new chromane derivatives. The reaction takes place through in situ formation of allene intermediates from the cyclopropanes and subsequent Michael-initiated ring closure of the intermediates with salicylaldehydes.

Tandem Dearomative/Rearomative (3 + 2) Annulation of Aroyl-Substituted Donor-Acceptor Cyclopropanes with Benzothiazoles.

A series of benzo[d]pyrrolo[2,1-b]thiazoles was synthesized by (3 + 2) annulation of aroyl-substituted donor-acceptor cyclopropanes with benzothiazoles. The annulation, promoted by a substoichiometric amount of Sc(OTf)3, takes place through the formation of the respective dearomatized (3 + 2) adducts, followed by unexpected decarbethoxylative and dehydrogenative rearomatization to afford fully aromatized products. The unusual reactivity is attributed to the presence of an extra aroyl group in the donor-acceptor cyclopropanes.

SnCl4-mediated one-pot synthesis of 2,4,5-trisubstituted thiazoles from nitro-substituted donor-acceptor cyclopropanes and thioamides.

The treatment of nitro-substituted donor-acceptor cyclopropanes (DACs) with SnCl4 and the subsequent reaction with thioamides provide one-pot access to various thiazole derivatives. Aroylmethylidene malonates were produced as intermediates in the reactions and they underwent conjugate addition followed by cyclocondensation with thioamides to afford the products. This work demonstrates the versatility of this class of cyclopropanes in synthesizing all three 1,3-azoles.

The Cloke-Wilson rearrangement of aroyl-substituted donor-acceptor cylopropanes containing arylethyl donors.

The chemistry of donor-acceptor (D-A) cyclopropanes containing alkyl donors has been scantily investigated. In the present work, we have synthesized new D-A cyclopropanes containing arylethyl donors and explored their reactivity in the presence of Lewis acids. Upon treatment with SnCl4, these cyclopropanes underwent the Cloke-Wilson rearrangement to yield 3,4,5-trisubstituted γ-butyrolactones in good yields with high diastereoselectivity.

Tin(iv) chloride mediated (3 + 2) annulation of trans-2-aroyl-3-styrylcyclopropane-1,1-dicarboxylates with nitriles: diastereoselective access to 5-vinyl-1-pyrroline derivatives.

A tin(iv) chloride promoted (3 + 2) annulation of trans-2-aroyl-3-styrylcyclopropane-1,1-dicarboxylates with nitriles is reported. The transformation involves the Lewis acid assisted formation of 1,5-dipolar intermediates from the cyclopropane dicarboxylates and nitriles followed by cyclization. The reactions proceed in a highly diastereoselective manner and afford 5-vinyl-1-pyrroline derivatives in 60-88% yields.

Scandium(III) Triflate-Catalyzed Reaction of Aroyl-Substituted Donor-Acceptor Cyclopropanes with 1-Naphthylamines: Access to Dibenzo[c,h]acridines.

The reaction of aroyl-substituted donor-acceptor (D-A) cyclopropanes with two equivalents of 1-naphthylamines in the presence of a catalytic amount of scandium(III) triflate provides access to dibenzo[c,h]acridines. The key steps of the transformation are the formation of nucleophilic ring-opening products from the D-A cyclopropanes and 1-naphthylamines and their subsequent fragmentation and cyclization. The method has a reasonable substrate scope, and the products are formed in 50-70% yields.

SnCl4-Promoted [3+2] Annulation of γ-Butyrolactone-Fused Donor-Acceptor Cyclopropanes with Nitriles: Access to γ-Butyrolactone-Fused 1-Pyrrolines.

The [3+2] annulation of γ-butyrolactone-fused donor-acceptor cyclopropanes with nitriles has been explored for the access of γ-butyrolactone-fused 1-pyrrolines. The annulation was promoted by tin(IV) chloride, and the products were obtained as single diastereomers in moderate to good yields. The products were synthetically important, and a couple of them were subjected to tandem reductive ring opening/cyclization to give the respective γ-butyrolactone-fused γ-butyrolactams in good yields.

Iodine-mediated synthesis of benzo[a]fluorenones from yne-enones.

The chalcones derived from o-alkynylacetophenones and aromatic aldehydes (yne-enones) when heated under reflux with iodine in acetic acid gave a range of benzo[a]fluorenone derivatives in moderate to good yields. The transformation involves the formation of a vinyl indenone intermediate through regioselective alkyne hydration and intramolecular aldol condensation followed by electrocyclic ring closure and aromatization.

Lewis Acid-Mediated Ring-Opening Reactions of trans-2-Aroyl-3-styrylcyclopropane-1,1-dicarboxylates: Access to Cyclopentenes and E,E-1,3-Dienes.

The ring-opening reaction of trans-2-aroyl-3-styrylcyclopropane-1,1-dicarboxylates was investigated with different Lewis acids. With SnCl4, the cyclopropane dicarboxylates afforded cyclopentene derivatives through ring opening followed by cyclization (vinylcyclopropane-cyclopentene rearrangement). With TiCl4, they furnished E,E-1,3-diene derivatives stereoselectively via ring opening followed by proton elimination.

Nucleophilic ring-opening reactions of trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates with hydrazines.

trans-2-Aroyl-3-aryl-cyclopropane-1,1-dicarboxylates when treated with arylhydrazines in refluxing EtOH gave dihydropyrazoles, whereas with hydrazines in refluxing AcOH, they formed cyclopropane-fused pyridazinones. Although in both cases the corresponding hydrazones are formed initially, the former case involves a subsequent 5-exo-tet nucleophilic ring-opening, and the later, a 6-exo-trig nucleophilic attack by the other hydrazone nitrogen. The products are obtained in moderate to excellent yields with complete regio-and diastereoselectivity.

Iron-Catalyzed Tandem Conia-Ene/Friedel-Crafts Reactions of o-Alkynyldihydrochalcones: Access to Benzo[b]fluorenes.

o-Alkynyldihydrochalcones when treated with a catalytic amount of anhydrous FeCl3 in refluxing 1,2-dichloroethane underwent tandem Conia-ene and Friedel-Crafts reactions to yield benzo[b]fluorene derivatives in good yields.

Synthesis of 2,4,5-trisubstituted oxazoles through tin(IV) chloride-mediated reaction of trans-2-aryl-3-nitro-cyclopropane-1,1-dicarboxylates with nitriles.

trans-2-Aryl-3-nitro-cyclopropane-1,1-dicarboxylates when reacted with nitriles in the presence of tin(IV) chloride afford 2,4,5-trisubstituted oxazoles in good to excellent yields. The reactions take place through in situ generation of aroylmethylidene malonates from the cyclopropanes, followed by conjugate addition of nitriles to the malonates to form nitrilium ion intermediates and subsequent cyclisation.

Synthesis of 3,3-disubstituted-2,3-dihydroazanaphthoquinones via simultaneous alkyne oxidation and nitrile hydration of ortho-alkynylarenenitriles.

o-Alkynylarenenitriles when heated with Pd(OAc)2/H2O/(±)-CSA in DMSO undergo simultaneous alkyne oxidation and nitrile hydration to give 3-aryl-3-hydroxy-2,3-dihydroazanaphthoquinones. Upon treatment with (±)-CSA, these compounds form 3-arylazanaphthoquinones in situ, which add to electron-rich aromatics and terminal alkene/alkyne to afford 3,3-disubstituted-2,3-dihydroazanaphthoquinones.

Boron trifluoride mediated ring-opening reactions of trans-2-aryl-3-nitro-cyclopropane-1,1-dicarboxylates. Synthesis of aroylmethylidene malonates as potential building blocks for heterocycles.

trans-2-Aryl-3-nitro-cyclopropane-1,1-dicarboxylates, upon treatment with BF3·OEt2, undergo ring-opening rearrangement and the Nef reaction to give aroylmethylidene malonates. The products are found to be potential precursors for heterocycles, such as imidazoles, quinoxalines, and benzo[1,4]thiazines.

[3+3] Annulation of donor-acceptor cyclopropanes with mercaptoacetaldehyde: application to the synthesis of tetrasubstituted thiophenes.

A conceptually new method for synthesis of tetrasubstituted thiophenes in two steps from trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol has been developed. It involves AlCl3-mediated [3+3] annulation of the cyclopropane-derived 1,3-zwitterionic intermediates with in situ generated mercaptoacetaldehyde, followed by DBU-induced rearrangement of the resulting tetrahydrothiopyranols. The target thiophenes are produced in 55-82% yields.